Intra-articular electrotransfer of mouse soluble tumour necrosis factor receptor in a murine model of rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and destruction of the joints. In the collagen-induced arthritis mouse model of RA, we developed a nonviral gene therapy method designed to block in situ the main cytokine tumour necrosis factor (TNF)-α Methods: Electrotransfer was used to deliver a plasmid encoding extracellular domain of mouse soluble TNF-α receptor type I fused to the Fc fragment of mouse immunoglobulin (Ig)G1 (pTNFR-Is) corresponding to a dimeric TNF-α soluble receptor fusion protein (mTNFR-Is/Ig). Results: Delivery of the plasmid into the knees at symptom onset improved the histological inflammation and destruction not only at the knees, but also at the ankles, indicating a local and a regional therapeutic effect. The plasmid was detected in synovialmembrane and meniscus specimens from the injected joints. In the synovial membrane, 15 days post-injection, interleukin (IL)-17 and TNF-α mRNAs expression were increased, whereas IL-10 mRNA was unchanged. However, the empty plasmid exerted a pro-inflammatory effect 30 days post-injection. Conclusions: These data indicate that local nonviral gene therapy against TNF-α is effective, although further work is needed to decrease plasmid induced inflammation.